This Program Project Grant application is founded on the hypothesis that endothelial cells derived from arterial, venous, and microcirculatory vessels are phenotypically distinct, and that these differences are critical determinants of their site-specific function. To date, limited consideration has been given to the idea that endothelial cells from different vascular segments within the lung may be phenotypically distinct. Rather, it is generally assumed that conduit endothelial cells represent a suitable model for study of microvascular endothelium-and hence the microcirculation, and that distinctions in cell behavior in vivo may be largely attributed to the microenvironment in which the different cells reside. However, compelling studies indicate that even under similar environmental conditions arterial, venule, and microvascular cells differ in their morphologies, proliferation rates, responses to growth and angiogenic factors, cyclic nucleotide regulatory mechanisms, calcium regulation, and other signaling pathways fundamental to the biology of endothelium. This application therefore encompasses three individual projects and three cores that collectively address whether inflammatory agonists (Projects 1-3), mechanical stress (Project 2), and oxidant stress (Project 3( activate) unique transduction pathways in arterial, venule and microvascular endothelial cells to differentially regulate their function. These projects are highly interactive both conceptually and pragmatically. Toward this end, this Program Project Grant draws on emerging developments in different fields of study, and applies these developments to generate new information about how macro- and microvascular lung endothelial cells respond to inflammation and how they repair following injury. The whole of these projects is greater than the sum of its parts; their collective outcome will provide a composite picture of whether macro- and microvascular endothelial cells respond to inflammatory stimuli using similar or different pathways and thereby lead to a better understanding of the pathogenesis and potential therapeutic strategies in acute lung injury.